NM_153676.4:c.*405C>A

Variant names:

• chr11-17493927-G-T
• rs11827649
• NM_153676.4:c.*405C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153676.4(USH1C):​c.*405C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 126,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: USH1C NM_153676.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.834
• Publications: 0 publications found

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C Gene-Disease associations (from GenCC):

• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.*405C>A		3_prime_UTR	Exon 27 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.*437C>A		3_prime_UTR	Exon 21 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.*437C>A		3_prime_UTR	Exon 22 of 22	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.*405C>A		3_prime_UTR	Exon 27 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.*437C>A		3_prime_UTR	Exon 21 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.*437C>A		3_prime_UTR	Exon 20 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000158 AC: 2 AN: 126560 Hom.: 0 Cov.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65296

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4978

American (AMR) AF: 0.00 AC: 0 AN: 7406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3344

East Asian (EAS) AF: 0.00 AC: 0 AN: 7708

South Asian (SAS) AF: 0.0000604 AC: 1 AN: 16564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 506

European-Non Finnish (NFE) AF: 0.0000135 AC: 1 AN: 74160

Other (OTH) AF: 0.00 AC: 0 AN: 6810

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.7
DANN	Benign	0.83
PhyloP100		0.83

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11827649; hg19: chr11-17515474;